KR20220170729A - A method of iron oxide magnetic particles - Google Patents

Abstract

In the present invention, provided is a manufacturing method of iron oxide magnetic particles, which comprises the following steps of: preparing particles containing iron oxide and MX_1n; mixing the particles containing the iron oxide and MX_1n to a solution containing AX_2n; and substituting X_1n and X_2n to form the iron oxide magnetic particles including the iron oxide and MX_2n. The present invention is to provide the manufacturing method for compensating for the short half-life of radioactive elements included in the iron oxide magnetic particles.

Description

Manufacturing method of iron oxide magnetic particles {A METHOD OF IRON OXIDE MAGNETIC PARTICLES}

The present invention relates to a method for producing iron oxide magnetic particles.

Magnetic particles have been widely used in biomedical fields including cell labeling, magnetic resonance imaging (MRI), drug delivery, and hyperthermia. Among various types of magnetic particles, superparamagnetic iron oxide based nanoparticles have been widely studied in the field of biomedicine because of their high magnetic susceptibility and superparamagnetism.

In addition, since magnetic particles have a characteristic of generating heat when radiation or a magnetic field is applied thereto, magnetic carriers for drug delivery in the field of magnetic resonance imaging (MRI) or nanomedicine, magnetic or radiation It can also be used for heat-based therapy and the like.

In the field of diagnostic imaging, iron oxide is proposed as a superparamagnetic contrast agent and a negative contrast agent. However, if the hydrophobic attraction is strong, they coagulate with each other to form clusters, or if they are not sufficiently stable due to rapid biodegradation when exposed to the living environment, the original structure may change and the magnetic properties may change, and they may have toxicity. On the other hand, iodine is proposed as a positive contrast agent, but when used in high concentrations to enhance the contrast effect, a formulation technology is being introduced to increase the content per volume of the contrast medium due to liver/kidney toxicity.

In the case of existing radioactive diagnostic/therapeutic agents, long-term storage or long-distance distribution is difficult due to their short half-life. Therefore, most medical institutions produce and use radioactive diagnostic/therapeutic agents daily as needed locally. However, in the case of radiopharmaceuticals prepared in this way, when administered into the body, the labeled radionuclide is separated and may cause side effects to other normal tissues.

Wust et al. Lancet Oncology, 2002, 3:487-497.

The problem to be solved by the present invention is to provide a manufacturing method to compensate for the short half-life of a radioactive element included in iron oxide magnetic particles.

In order to solve the above problems, the present invention comprises the steps of preparing particles containing iron oxide and MX _1n , mixing the particles containing iron oxide and MX _1n in a solution containing AX _2n , and the X _1n and X _2n Substituted to form iron oxide magnetic particles including iron oxide and MX _2n It provides a method for producing iron oxide magnetic particles.

The manufacturing method of iron oxide magnetic particles of the present invention can rapidly replace radioactive elements having a short half-life, thereby increasing the field utilization of iron oxide magnetic particles.

In addition, in the iron oxide magnetic particles manufactured according to the present invention, since halogen particles containing radioactive isotopes can be formed very densely in the iron oxide core, stability of the manufactured iron oxide magnetic particles can be excellently secured.

1 is a result of XPS component analysis of iron oxide magnetic particles of Preparation Example 1.
2 is a result of XPS component analysis of the iron oxide magnetic particles of Example 3.
3 is a TEM photograph of Example 3.
4 is an EDS component analysis photograph of Example 3.
5 is a hydration size distribution chart of Example 3.
6 is a result of XPS component analysis of iron oxide magnetic particles of Comparative Example 3;

Hereinafter, various embodiments of the present invention will be described with reference to the accompanying drawings. It should be understood that the present invention is not limited to specific embodiments, and includes various modifications, equivalents, and/or alternatives of the embodiments of the present invention. In connection with the description of the drawings, like reference numerals may be used for like elements.

In this document, expressions such as "has", "may have", "includes", or "may include" refer to the presence of a corresponding feature (eg, numerical value, function, operation, or component such as a part). , which does not preclude the existence of additional features.

In this document, expressions such as "A or B", "at least one of A and/and B", or "one or more of A or/and B" may include all possible combinations of the items listed together. . For example, "A or B", "at least one of A and B", or "at least one of A or B" includes (1) at least one A, (2) at least one B, Or (3) may refer to all cases including at least one A and at least one B.

The expression "configured to" as used in this document means, depending on the circumstances, e.g. "Suitable for", "Having the capacity to" ", "Designed to", "Adapted to", "Made to", or "Capable of" may be used interchangeably. The term "configured (or set) to" does not necessarily mean "specifically designed to."

Terms used in this document are only used to describe a specific embodiment, and may not be intended to limit the scope of other embodiments. Singular expressions may include plural expressions unless the context clearly dictates otherwise. Terms used herein, including technical or scientific terms, may have the same meaning as commonly understood by a person of ordinary skill in the technical field described in this document. Among the terms used in this document, the terms defined in general dictionaries may be interpreted as having the same or similar meaning to the meaning in the context of the related art, and unless explicitly defined in this document, in an ideal or excessively formal meaning. not interpreted In some cases, even terms defined in this document cannot be interpreted to exclude the embodiments of this document.

The embodiments disclosed in this document are presented for explanation and understanding of the disclosed technical content, and do not limit the scope of the present invention. Therefore, the scope of this document should be construed to include all changes or various other embodiments based on the technical idea of the present invention.

Hereinafter, preferred embodiments of the present invention will be described in detail. Prior to this, the terms or words used in this specification and claims should not be construed as being limited to the usual or dictionary meaning, and the inventor appropriately uses the concept of the term in order to explain his/her invention in the best way. It should be interpreted as a meaning and concept consistent with the technical idea of the present invention based on the principle that it can be defined.

Therefore, since the configurations of the embodiments described in this specification are only some of the most preferred embodiments of the present invention and do not represent all of the technical spirit of the present invention, various equivalents and modifications that can replace them at the time of this application It should be understood that there may be

Throughout the specification, when a certain component is said to "include", it means that it may further include other components without excluding other components unless otherwise stated.

In one aspect of the present disclosure, the term "about" is used with the intention of including a slight numerical adjustment that falls within the scope of a manufacturing process error included in a specific value or the scope of the technical spirit of the present disclosure. For example, the term “about” means a range of ±10%, in one aspect ±5%, and in another aspect ±2% of the value to which it refers.

Hereinafter, the present invention will be described in detail.

A method of manufacturing iron oxide magnetic particles according to an embodiment of the present invention includes the steps of preparing particles containing iron oxide and MX _1n , mixing the particles containing iron oxide and MX _1n with a solution containing AX _2n , and the above steps. X _1n and X _2n may be substituted to form iron oxide magnetic particles including iron oxide and MX _2n .

M includes at least one selected from the group consisting of Cu, Sn, Pb, Mn, Ir, Pt, Rh, Re, Ag, Au, Pd, and Os, and X ₁ or X ₂ is F, Cl, It includes at least one selected from the group consisting of Br and I, and n may be an integer from 1 to 6.

X ₁ may be more reactive than X ₂ , and X ₁ may have a smaller ionic radius than X ₂ . Specifically, when X ₁ is F, X ₂ may be Cl, Br or I, and when X ₁ is Cl, X ₂ may be Br or I.

MX _1n includes one or more selected from the group consisting of CuF, CuF ₂ , CuF ₃ , CuCl, and CuCl ₂ , and MX _2n is selected from the group consisting of CuBr, CuBr ₂ , CuI, CuI ₂ and CuI ₃ It may include one or more selected from.

A is an alkali or alkaline earth element, and specifically, may include one or more selected from the group consisting of Li, Na, K, Ru, Cs, Fr, Be, Mg, Ca, Sr, Ba, and Ra. .

In addition, the present invention provides iron oxide magnetic particles formed by the above manufacturing method.

The "iron oxide" is an oxide of iron, for example, Fe ₁₃ O ₁₉ , Fe ₃ O ₄ (magnetite), γ-Fe ₂ O ₃ (maghemite) and α-Fe ₂ O ₃ (hematite), β-Fe ₂ O ₃ (beta phase), ε-Fe ₂ O ₃ (epsilon phase), FeO (Wustite), FeO ₂ (Iron Dioxide), Fe ₄ O ₅ , Fe ₅ O ₆ , Fe ₅ O ₇ , Fe ₂₅ O ₃₂ , ferrite type (Ferrite type) and may include one or more selected from the group consisting of Delafossite, but is not limited thereto.

Particles containing MX _2n in iron oxide particles have magnetism and can amplify the contrast effect of iron oxide under a relatively low strength and/or low frequency magnetic field or various radiation conditions.

In addition, the X ₁ or X ₂ may include a radioactive isotope or a radioactive isotope mixture of X. Specifically, it refers to a compound in which one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of fluorine, such as ¹⁸ F; Isotopes of chlorine, such as ³⁶ Cl; isotopes of bromine such as ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br; and isotopes of iodine, such as ¹²³ I, ¹²⁴ I, ¹²⁵ I, and ¹³¹ I alone or in combination.

Each of the isotopes of F, Br, Cl, and I, which do not emit radiation in nature, have half-lives of only tens of minutes to several days. Therefore, when iron oxide magnetic particles containing a radioactive isotope are manufactured in advance, time elapses in the distribution stage, so the radiation emission rate may be significantly lowered at the time when the actual demand is needed. In particular, since the iron oxide magnetic particles of the present invention can be delivered to various medical institutions and injected into patients, a decrease in radiation efficiency can be a very important problem.

The step of preparing the particles including iron oxide and MX _1n is to synthesize a precursor prior to replacing Mx _1n with MX _2n , as long as MX _1n is included in the iron oxide, specifically through the following process. may be preparing

Here, the fact that MX _n (MX _1n or MX _2n ) is included in the iron oxide particle may mean that a physical or chemical bond is formed between the iron oxide particle and MX _n . Specifically, MX _n may be disposed between iron oxide particles, or iron oxide and MX _n may be bonded through hydrogen bonding. MX _n may be formed by introducing a general coating method on the surface of the iron oxide core, or diffusion It may be formed by introducing a doping process such as a process or an ion implantation process, or may include forming iron oxide crystal nuclei inside MX _n to form a shell structure.

Specifically, in order to prepare a complex of iron and one or more compounds selected from the group consisting of aliphatic hydrocarbonates having 4 to 25 carbon atoms and amine compounds, a hydrate of iron, which is a precursor of iron oxide, is prepared, and the hydrate of iron An iron complex can be obtained by mixing and reacting an aliphatic hydrocarbon acid salt having 4 to 25 carbon atoms and an amine-based compound. Thereafter, mixing the obtained composite with MX _1n and heating to oxidize iron to introduce MX _1n into iron oxide may be included. The complex of iron with at least one compound selected from the group consisting of the aliphatic hydrocarbon acid salts and amine-based compounds is, for example, an aliphatic hydrocarbon acid salt having 4 to 25 carbon atoms and an amine-based compound in FeCl ₃ 6H ₂ O, which is an iron hydrate. It may be a complex obtained by mixing and then reacting one or more compounds selected from the group consisting of compounds. For example, an iron-oleic acid complex may be obtained by reacting sodium oleate with FeCl ₃ ·6H ₂ O. Thereafter, iron is oxidized by reacting the iron-oleic acid complex with MX _1n to form iron oxide, and MX _1n may be included in the formed iron oxide.

Examples of the aliphatic hydrocarbon acid salts having 4 to 25 carbon atoms include butyrate, valerian acid, caproate, enanthate, caprylic acid, pelargonic acid, caprate, laurate, myristate, pentadecylate, and acetic acid. salt, palmitate, palmitoleate, margarate, stearate, oleate, baxenate, linoleate, (9,12,15)-linolenate, (6,9,12)-linolenate, eleoste Arates, tubeculostearates, rakidates, arachidonates, behenates, lignocerates, nervonates, cerotates, montanates, melisates and peptide salts containing one or more amino acids. It may include one or more selected from the group consisting of. These 　 compounds may be used alone or in the form of a mixed acid salt of two or more kinds.

The metal component of the aliphatic hydrocarbon acid salt having 4 to 25 carbon atoms may include one or more selected from the group consisting of calcium, sodium, potassium and magnesium.

Examples of the amine compound include methylamine, ethylamine, propylamine, isopropylamine, butylamine, amylamine, hexylamine, octylamine, 2-ethylhexylamine, nonylamine, decylamine, laurylamine, and pentadecylamine. Amine, cetylamine, stearylamine and cyclohexylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diamylamine, dioctylamine, di(2-ethylhexyl)amine , didecylamine, dilaurylamine, disetylamine, distearylamine, methylstearylamine, ethylstearylamine and butylstearylamine, triethylamine, triamylamine, trihexylamine and trioctylamine, triallylamine and oleylamine, laurylaniline, stearylaniline, triphenylamine, N,N-dimethylaniline and dimethylbenzylaniline, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, Diethylenetriamine, triethylenetetramine, tetraethylenepentamine, benzylamine, diethylaminopropylamine, xylylenediamine, ethylenediamine, hexamethylenediamine, dodecamethylenediamine, dimethylethylene Diamine, triethylenediamine, guanidine, diphenylguanidine, N,N,N',N'-tetramethyl-1,3-butanediamine, N,N,N',N'-tetramethylethylenediamine , 2,4,6-tris(dimethylaminomethyl)phenol, morpholine, N-methylmorpholine, 2-ethyl-4-methylimidazole and 1,8-diazabicyclo (5,4,0) It may include one or more selected from the group consisting of undecene-7 (DBU).

In the iron oxide magnetic particles of the present invention, the MX _2n is about 1 to 13 mol%, preferably about 1 to 13 mol%, based on 100 mol% of a complex of iron and one or more compounds selected from the group consisting of aliphatic hydrocarbonates having 4 to 25 carbon atoms and amine compounds. Preferably, it may be prepared by including about 1 to 6 mol%, more preferably about 3 to 6 mol%.

The step of mixing the iron oxide and the particles containing MX _1n in a solution containing AX _2n is a chemical process in which X _1n and X _2n are replaced by reacting the iron oxide prepared in the above step with the particles containing MX _1n and AX _2n . A reaction is induced to form iron oxide magnetic particles containing iron oxide and MX _2n . Here, the chemical reaction may be performed through a heating process, or a process time may be shortened using a microwave.

Specifically, in the above step, after dispersing particles including iron oxide and MX _1n in a hydrophobic solvent, a solution containing AX _2n is added to a hydrophilic solvent as a solvent, and X _1n is dissolved by heating or using a microwave. as X _2n It may be to perform a process of substitution.

The hydrophobic solvent is toluene, hexane, octane, heptane, tetradecane, chloroform, methyl chloride, butyl carbitol acetate, ethyl carbitol acetate, terpineol (α-Terpineol) and acetone It may include one or more selected from the group consisting of.

Since the surface of the particles containing iron oxide and MX _1n has a hydrophobic property, it is preferable to use the hydrophobic solvent to soften the bond between the particles containing iron oxide and MX _1n while easily dispersing them. From the viewpoint of compatibility with a solution containing AX _2n as a hydrophilic solvent, toluene, hexane and chloroform are preferred.

During the dispersion, the weight ratio between the particles containing iron oxide and MX _1n and the hydrophobic solvent is preferably adjusted to 1:200 to 700. If it is less than the above range, the bonding of the particles including iron oxide and MX _1n may not be weakened, so that the subsequent replacement process may not be easily performed. may not be transferred to particles comprising iron oxide and MX _1n .

If it is less than the above range, the distance between the particles in the solvent containing iron oxide and MX _1n is dense, so that dispersibility may decrease and aggregation may occur, so that the subsequent substitution process may not be easily performed. If it exceeds the above range, the excessive solvent content Due to this, energy during heating or microwave irradiation may not be transferred to particles containing iron oxide and MX _1n .

The hydrophilic solvent may include purified water, glycerol, methanol, and ethanol, and deionized water is preferably used as the purified water.

After the particles made through the step of preparing the particles containing the iron oxide and MX _1n are stored for a long time or subjected to a long-term distribution (eg, air transportation, etc.), they are just manufactured in the transported area and emit the highest radiation While possible, it may be mixed with a solution containing X _2n having a short half-life (solution containing AX _2n ) and treated.

According to the above manufacturing method, the amount of radiation that can be lost in a long-term distribution process (or decay according to the half-life of a radioactive element) can be easily replaced by a substitution method on the spot. In addition, rather, by using such a substitution method, the ratio of X _2n bonded to iron oxide can be significantly increased compared to particles formed from a conventional manufacturing method.

In addition, as another example of the present invention, it may be very easy to include different isotopes of radioactive isotopes bound to iron oxide magnetic particles according to usage. For example, as X _2n , ¹²⁴ I can be used for PET imaging diagnosis, ¹²⁵ I can be used for SPECT imaging diagnosis, and ¹³¹ I can be used for thyroid cancer treatment, so iron oxide and MX _1n are included first. It is possible to prepare the final iron oxide magnetic particles by manufacturing particles to be used, and easily substituting X _2n (radiation isotope half-life not yet reached), which is possessed by a medical institution to apply the particles through a distribution process, according to the place of use. can

Specifically, since ¹³¹ I used for thyroid cancer treatment has a very short half-life of 8 days, rather than manufacturing and distributing magnetic particles containing iron oxide and Cu ¹³¹ I, iron oxide and CuF ₂ (a radioactive isotope) After first preparing magnetic ^particles containing 19 F) other than ¹⁹ F), the ^iron oxide and the iron oxide and Particles containing CuF ₂ are mixed and reacted, and ¹³¹ I and F are substituted. From these results, magnetic particles containing iron oxide and Cu ¹³¹ I can be directly applied to patients in the medical field.

In particular, according to an embodiment of the present invention, since the surface of the particles including iron oxide and MX1n has a hydrophobic property, the hydrophobic solvent is used to soften the bond between the particles including iron oxide and MX1n while easily dispersing them. It is preferable, and in order to more easily mix the solution containing AX2n in the hydrophilic solvent applied later, a hydrophilic ligand containing both a hydrophilic part and a hydrophobic part in the molecular structure and exhibiting surfactant properties is mixed process may be included.

Specifically, when the process is performed by dispersing particles containing iron oxide and MX1n in a hydrophobic solvent and then adding only a solution containing AX2n to the hydrophilic solvent as a solvent, mixing of the hydrophilic part and the hydrophobic part may become difficult. The hydrophilic ligand may be introduced to increase the solubility and stabilization of the particle including iron oxide and MX1n in a hydrophilic solvent. Due to the introduction of the hydrophilic ligand, a higher substitution rate of X2n in iron oxide magnetic particles including finally obtained iron oxide and MX2n can be secured.

Specifically, after dispersing the particles containing iron oxide and MX1n in a hydrophobic solvent, a solution containing a hydrophilic solvent, a hydrophilic ligand, and AX2n as a solvent is mixed with a hydrophobic solvent and the particles containing iron oxide and MX1n are heated or irradiated with a microwave. It may be to perform the process of

In addition, the above process of the present invention may be introduced to provide that at least a portion of the finally obtained surface of the iron oxide particle is coated with a hydrophilic or charged ligand or polymer, targeting or targeting specific cells such as cancer cells. It can be introduced to enhance penetration.

Such hydrophilic ligands may preferably be biocompatible, and include, for example, polyethylene glycol, polyethyleneamine, polyethyleneimine, polyacrylic acid, polymaleic anhydride, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl amine, poly Acrylamide, polyethylene glycol, phosphoric acid-polyethylene glycol, polybutylene terephthalate, polylactic acid, polytrimethylene carbonate, polydioxanone, polypropylene oxide, polyhydroxyethyl methacrylate, starch, dextran derivatives, sulfonic acid It may include at least one selected from the group consisting of amino acids, sulfonic acid peptides, silica, and polypeptides, but is not limited thereto. If necessary, in the case of targeting cancer cells, a peptide or protein including folic acid, transferrin or RGD may be used as the hydrophilic ligand, and hyaluronidase or collagenase may be used to enhance cell penetration. can be used, but is not limited thereto.

In one embodiment, the iron oxide magnetic particles may be included in a weight ratio of MX _2n to iron oxide, 1:0.005 to 0.08, preferably 1:0.01 to 0.08 (the ratio is ICP, a metal content analyzer) (inductively coupled plasma) assigned based on mass spectroscopy results). By being included within the above range, excellent specific loss power can be secured, and high temperature change can be secured under an external alternating magnetic field or when irradiated with radiation.

In one embodiment, the iron oxide magnetic nanoparticles may have a diameter of 3 to 100 nm. The size of the diameter can be adjusted according to the method of administration, the location of administration, and the organ to be diagnosed. For example, intravenous injection is preferred if the diameter is less than 15 nm, and intralesional or intratumor injection may be preferred if the diameter is greater than 15 nm.

According to another embodiment of the present invention, the step of mixing the iron oxide and MX _1n -containing particles in a solution containing AX _2n further includes the above-described hydrophilic ligand so that the atoms of X _1n and X _2n in the iron oxide magnetic particles Substitution and coating of hydrophilic ligands may be carried out in parallel.

Hereinafter, examples and the like will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Examples and Comparative Examples

Preparation Example 1

Formation of iron-oleic acid complex

16.218 g of FeCl ₃ 6H ₂ O, 54.79 g of sodium oleate, 224 ml of hexane, 120 ml of ethanol, and 90 ml of deionized water were mixed and reacted at 110 ° C. for 6 hours with vigorous stirring. After cooling the reaction solution at room temperature, the transparent lower layer was removed using a separatory funnel, and 100 ml of water was mixed with the brown upper organic layer, shaken, and the lower water layer was removed again. This was repeated 3 times. The remaining brown organic layer was transferred to a beaker and heated at 110 °C for 4 hours to evaporate hexane.

CuF ₂ Synthesis of iron oxide magnetic particles containing

4.5 g (5 mmol) of the iron-oleic acid complex prepared above and 0.8 ml (2.5 mmol) of oleic acid were mixed. 30.5 mg (0.3 mmol) of CuF ₂ was added and mixed with 15 ml of 1-octadecene. The mixed solution was put into a round bottom flask and gas and moisture were removed in a vacuum at 90 °C for about 30 minutes. Nitrogen was injected and the temperature was raised to 200 °C. Thereafter, the temperature was raised to 320 °C at a rate of 3.3 °C/min and reacted for 30 minutes. After cooling the reaction solution, it was transferred to a 50 ml conical tube, and 30 ml of ethanol and hexane were injected at a ratio of 2:1, followed by centrifugation to precipitate particles. After washing the precipitated particles with 10 ml of hexane and 5 ml of ethanol, the obtained precipitate was dispersed in toluene or hexane. The size of the prepared particles was 8 nm. This was referred to as Production Example 1.

Example 1

CuF ₂ Iron oxide magnetic particles containing Na ¹³¹ Substitute I

10 mg of iron oxide magnetic particles containing CuF ₂ obtained in Preparation Example 1 were dispersed in 3 mL of chloroform (specific gravity: 1.5), and 2 mL of deionized water and 1 ml of Na ¹³¹ I (185 MBq (5 mCi)) were put into a 50 mL vial and microwaved at 2.4 GHz 1000 W. It works for 1 minute.

After removing the solution using an evaporator, 3ml of deionized water is added and sonication is performed for 5 minutes to disperse. After dispersing, put ethanol and deionized water in Amicon 100k in a ratio of 2:8 and wash using centrifugal separation (5,000 rpm, 5 m). The resulting product was put into Amicon 100k again with deionized water and washed using centrifugation (5,000 rpm, 5 m) to obtain iron oxide particles containing Cu ¹³¹ I.

Example 2

CuF ₂ Iron oxide magnetic particles containing Na ¹³¹ substituted with I and coated with Lipid PEG

10 mg of iron oxide magnetic particles containing ^CuF ₂ were dispersed in 3 mL of chloroform, ^and DSPE-PEG2000 (1,2-distearoyl Put -sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000) in a 50mL vial and operate for 1 minute with Microwave 2.4GHz 1000W.

After removing the solution using an evaporator, 3ml of deionized water is added and sonication is performed for 5 minutes to disperse. After dispersing, put ethanol and deionized water in Amicon 100k in a ratio of 2:8 and wash using centrifugal separation (5,000 rpm, 5 m). The resulting product was put into Amicon 100k again with deionized water and washed using centrifugation (5,000 rpm, 5 m) to obtain iron oxide nanoparticles.

Example 3

CuF ₂ Iron oxide magnetic particles containing Na ¹²⁷ substituted with I and coated with Lipid PEG

10 mg of iron oxide magnetic particles containing ^CuF ₂ were dispersed in 3 mL of chloroform, ^{and DSPE} -PEG2000 (1, Put 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000) in a 50mL vial and operate for 1 minute with Microwave 2.4GHz 1000W.

After removing the solution using an evaporator, 3ml of deionized water is added and sonication is performed for 5 minutes to disperse. After dispersing, put ethanol and deionized water in Amicon 100k in a ratio of 2:8 and wash using centrifugal separation (5,000 rpm, 5 m). The resulting product was put into Amicon 100k again with deionized water and washed using centrifugation (5,000 rpm, 5 m) to obtain iron oxide nanoparticles.

Example 4

CuF ₂ Iron oxide magnetic particles containing Na ¹²⁷ substituted with I and coated with Lipid-PEG-carboxymethyl dextran

10 mg of iron oxide magnetic particles containing CuF ₂ were dispersed in 3 mL of chloroform, and DSPE-PEG2000-carboxymethyl dextran was added to a 50 mL vial at a ratio of 2 mL of deionized water, 20 mg of Na ¹²⁷ I, and 8 particles per particle surface area (1 nm ² ), and Microwave 2.4 GHz 1000 W It works for 1 minute with After removing the solution using an evaporator, 3ml of deionized water is added and sonication is performed for 5 minutes to disperse. After dispersing, put acetone and deionized water in a ratio of 2:8 in Amicon 100k and wash using centrifugal separation (5,000 rpm, 5 m). The resulting product was put into Amicon 100k again with deionized water and washed using centrifugal separation (5,000 rpm, 5 m).

Examples 6 to 10 and Comparative Examples 1 to 2

It was carried out under the same conditions as in Example 1, but the type or amount of chloroform introduced was changed as shown in the table below to prepare iron oxide magnetic particles.

note Solvent type (specific gravity, 20℃) Solvent content (ml) (iron oxide magnetic particles containing CuF ₂ : solvent weight ratio) Example 5 Chloroform (1.5) 2 ml (1:300) Example 5 Chloroform (1.5) 4ml (1:600) Example 7 Chloroform (1.5) 0.66 ml (1 : 100) Example 8 Chloroform (1.5) 5.33ml (l : 800) Example 9 Toluene (0.87) 5.17 ml (1:450) Comparative Example 1 Methanol (0.80) 5.63 ml (1:450) Comparative Example 2 Ethanol (0.79) 5.70 ml (1:450)

Example 10

CuF ₂ Iron oxide magnetic particles containing Na ¹³¹ Replaced with I and coated with Lipid-PEG-Folate

10 mg of iron oxide magnetic particles containing CuF ₂ were dispersed in 3 mL of chloroform, and DSPE-PEG2000-Folate was prepared in a ratio of 2 mL of deionized water, 1 ml of Na ¹³¹ I (185 MBq (5 mCi)), 20 mg per particle surface area (1 nm ² ), and 8 pieces of DSPE-PEG2000-Folate in a 50 ml vial. Put it in and operate for 1 minute with Microwave 2.4GHz 1000W. After removing the solution using an evaporator, 3ml of deionized water is added and sonication is performed for 5 minutes to disperse. After dispersing, put acetone and deionized water in a ratio of 2:8 in Amicon 100k and wash using centrifugal separation (5,000 rpm, 5 m). The resulting product was put into Amicon 100k again with deionized water and washed using centrifugal separation (5,000 rpm, 5 m).

Example 11

CuF ₂ Iron oxide magnetic particles containing Na ¹³¹ Replaced with I and coated with Lipid-PEG-Glucose

10 mg of iron oxide magnetic particles containing CuF ₂ were dispersed in 3 mL of chloroform, and DSPE-PEG2000-Glucose was mixed in 2 mL of deionized water, 1 ml of Na ¹³¹ I (185 MBq (5 mCi)), 20 mg, and 8 particles per particle surface area (1 nm ² ) in a 50 ml vial. Put it in and operate for 1 minute with Microwave 2.4GHz 1000W. After removing the solution using an evaporator, 3ml of deionized water is added and sonication is performed for 5 minutes to disperse. After dispersing, put acetone and deionized water in a ratio of 2:8 in Amicon 100k and wash using centrifugal separation (5,000 rpm, 5 m). The resulting product was put into Amicon 100k again with deionized water and washed using centrifugal separation (5,000 rpm, 5 m).

Comparative Example 3

Iron oxide particles according to the following manufacturing method were used as Comparative Example 1.

(a) Synthesis of iron-oleic acid complex (iron oleate)

FeCl ₃ .6H ₂ O (30 mmol) and sodium oleate (28 mmol) were mixed with 200 ml of hexane, 100 ml of ethanol, and 100 ml of deionized water and reacted at 110° C. for 6 hours with vigorous stirring. After cooling the reaction solution at room temperature, the transparent lower layer was removed using a separatory funnel, and the upper brown organic layer was mixed with 100 ml of water, shaken, and then the lower water layer was removed again. This was repeated 3 times. The remaining brown organic layer was transferred to a beaker and heated at 110 °C for 4 hours to evaporate hexane.

(b) Synthesis of iron oxide magnetic particles doped with Cu ₁₂₇ I

4.5 g (5 mmol) of iron-oleic acid complex, 1.7 g (6 mmol) of oleic acid, and 0.05 g (0.3 mmol) of Cu ¹²⁷ I were mixed with 7 ml of 1-eicosene and 13 ml of dibenzyl ether. The mixed solution was put into a round bottom flask and gas and water were removed in a vacuum at 90° C. for about 30 minutes. Nitrogen was injected and the temperature was raised to 200°C. Thereafter, the temperature was raised to 310 °C at a rate of 3.3 °C/min and reacted for 60 minutes. After cooling the reaction solution, it was transferred to a 50 ml conical tube, and 30 ml of ethanol and hexane were injected at a ratio of 1:1, followed by centrifugation to precipitate particles. After washing the precipitated particles with 10 ml of hexane and 5 ml of ethanol, the obtained precipitate was dispersed in toluene or hexane. Here, dibenzyl ether is decomposed into benzyl aldehyde and toluene at a temperature of 150 ° C or higher, and hydrogen bonds are formed between iron oxo (-Fe-OFe-) and heavy atom-halogen compounds (Cu ¹²⁷ I) by radicals generated from the aldehyde. assist in the formation of decisions. The size of the particles prepared in Example 1 was about 6-7 nm.

(C) PEG coating

10 mg of iron oxide magnetic particles containing Cu ¹²⁷ I were dispersed in 3 mL of chloroform, and DSPE-PEG2000 (1,2-distearoyl-sn-glycero-3-p xhosphoethanolamine-N Put -[methoxy(polyethylene glycol)-2000) in a 50mL vial and stir at room temperature.

After removing the solution by using an evaporator, add 3ml of deionized water and disperse it by “sonication” for 5 minutes. After dispersing, put ethanol and deionized water in Amicon 100k in a ratio of 2:8 and wash using centrifugation (5,000 rpm, 5 m). The resulting product was again put into Amicon 100k with deionized water and washed using centrifugation (5,000 rpm, 5 m) to obtain iron oxide nanoparticles.

Experimental example

Experimental Example: Iron oxide and MX under an external alternating magnetic field _2n Analysis of temperature change according to the weight ratio of

The particles prepared in Examples and Comparative Examples were tested for self-induction heating ability. After diluting each of Examples and Comparative Examples in deionized water to a concentration of 20 mg/ml, an alternating magnetic field was applied, and the temperature change was measured using a thermocouple (OSENSA, Canada). (Alternating current frequency and magnetic field strength: f = 108.7 kHz, H = 11.4 kA/m) The results are shown in Table 2 below.

The heating system by inducing an alternating magnetic field consists of four main subsystems; (a) a variable frequency and amplitude sine wave function generator (20 MHz Vp-p, TG2000, Aim TTi, USA), (b) a power amplifier (1200Watt DC Power Supply, QPX1200SP, Aim TTi, USA), (c) induction coil (number of revolutions: 17, diameter: 50 mm, height: 180 mm) and magnetic field generator (Magnetherm RC, nanoTherics, UK), (d) temperature change thermocouple (OSENSA, Canada) .

Temperature reached per unit time
(Standard: 1 minute)
Start measurement at 25°C Example 1 75 Example 2 85 Example 3 90 Example 4 85 Example 5 70 Example 6 72 Example 7 37 Example 8 40 Example 9 80 Example 10 82 Example 11 83 Comparative Example 1 29 Comparative Example 2 30 Comparative Example 3 51

Experimental Example: Measurement of Specific Loss Power (SLP)

Since the calorific value of particles varies depending on the physical and chemical characteristics and the strength and frequency of an external alternating magnetic field, most research results show the calorific power of particles as SLP and ILP. SLP is the electromagnetic force lost per unit of mass, expressed in Watts (W) per kg. Since the conditions of f (frequency) and H (magnetic field strength) may be different for each experiment in comparing the thermal treatment effect between particles, the SLP value is converted into the ILP value using the equation [ILP= SLP/( f H ² )] can be compared by

For the SLP measurement, an alternating magnetic field generator (Magnetherm RC, Nanotherics) of a series resonant circuit controlled by a pick-up coil and an oscilloscope was used. It was measured under adiabatic conditions of f = 108.7 kHz and H = 11.4 kA/m, and the temperature was measured using an optical fiber IR probe.

SLP was measured by adjusting the concentration of the particles of Examples and Comparative Examples to 20 mg/ml. The results are shown in Table 3 below.

ILP value Example 1 8.6 Example 2 9.75 Example 3 10.3 Example 4 9.75 Example 5 8.03 Example 6 8.26 Example 7 4.24 Example 8 4.59 Example 9 9.18 Example 10 9.38 Example 11 9.5 Comparative Example 1 3.32 Comparative Example 2 3.33 Comparative Example 3 5.85

Experimental Example: Microwave Stability Analysis of Iron Oxide Magnetic Particles

The particles of the Examples, Comparative Examples, and Control were irradiated for 15 minutes each at 2,400 to 2,500 MHz and 1000 W conditions using a microwave device made in the US by CEM. After microwave irradiation, the content of halogen elements was measured in a prodigy High Dispersion ICP measuring instrument equipped with a halogen option from A Teledyne Leeman Labs, and it was confirmed whether the particles disintegrated. The results are shown in Table 4.

note Measured halogen elements (ppm) Example 1 12 Example 2 4 Example 3 2 Example 4 5 Example 5 10 Example 6 10 Example 7 20 Example 8 22 Example 9 11 Example 10 3 Example 11 4 Comparative Example 1 22 Comparative Example 2 25 Comparative Example 3 30 Control 1 (iron oxide Fe ₃ O ₄ ) 0 Control 2 (doped with iron oxide-KI 6% by weight) 65 Control 3 (iron oxide-doped with MgI ₂ 6% by weight) 57

Experimental Example: Radiation dose measurement of iron oxide magnetic particles

The iron oxide magnetic particles of the above Examples, Comparative Examples, and Control were measured per 1 mg of Fe of each iron oxide magnetic particle using a gamma ray meter (Gamma Counter, 1480 Wizard 3) made in the US by Perkin Elmer, which is an equipment capable of measuring ¹³¹ I radiation dose. The radiation dose (mCi) was confirmed by measuring gamma rays. Thus, the bonding strength of ¹³¹ I could be confirmed. The results are shown in Table 5.

Radiation dose (mCi)/ Fe 1mg Example 1 105 Example 2 112 Example 3 0 Example 4 0 Example 5 98 Example 6 95 Example 7 58 Example 8 62 Example 9 103 Example 10 108 Example 11 106 Comparative Example 1 33 Comparative Example 2 30 Comparative Example 3 45

The XPS component analysis results of the iron oxide magnetic particles of Preparation Example 1 and Example 3 are shown in FIGS. 1 and 2, respectively. In the case of XPS component analysis, since XPS analysis is difficult for iron oxide applied with ¹³¹ I, a radioactive isotope, Example 3 using ¹²⁷ I with the same chemical propensity (only differences in radioactive isotope) was analyzed.

As can be seen in FIG. 1 , it was confirmed that iron oxide magnetic particles including iron oxide and CuF ₂ were formed from Preparation Example 1. Looking at the Fe 2P scan results of FIG. 1 , it can be confirmed that iron oxide is present, it can be confirmed that Cu is combined with iron oxide from the Cu 2p scan results, and it can be confirmed from the F 1s scan that CuF ₂ is formed.

As can be seen in FIG. 2 , it was confirmed that iron oxide magnetic particles including iron oxide and Cu ¹²⁷ I were formed from Example 3. Looking at the Fe 2P scan result of FIG. 1, it can be confirmed that iron oxide exists, it can be confirmed that Cu is combined with iron oxide from the Cu 2p scan result, and it can be confirmed that CuI is formed from the I 3d scan.

The TEM picture of Example 3 is shown in FIG. 3 .

EDS component analysis pictures of Example 3 are shown in FIG. 4 . As a result of the EDS mapping, it was confirmed that Fe and O, which are the main components of the iron oxide magnetic particles including Cu ¹²⁷ I, were confirmed, and it was confirmed that CuI was formed through the Cu and I mapping results.

The hydration size distribution map of Example 3 is shown in FIG. 5.

The results of XPS component analysis of the iron oxide magnetic particles of Comparative Example 3 are shown in FIG. 6 . As can be seen in FIG. 6 , it was confirmed that iron oxide magnetic particles including iron oxide and Cu ¹²⁷ I were formed from Example 3. Looking at the Fe 2P scan result of FIG. 6, it can be confirmed that iron oxide exists, it can be confirmed that Cu is combined with iron oxide from the Cu 2p scan result, and it can be confirmed that CuI is formed from the I 3d scan. However, in the case of Comparative Example 3, it can be seen that the substitution efficiency of I is relatively low compared to Example 3, and the intensity of the I 3d scan peak is relatively low.

Claims (7)

Preparing particles containing iron oxide and MX _1n ;
Mixing particles containing iron oxide and MX _1n in a solution containing AX _2n and
and forming iron oxide magnetic particles including iron oxide and MX _2n by substituting X _1n and X _2n .
The method of claim 1,
M includes at least one selected from the group consisting of Cu, Sn, Pb, Mn, Ir, Pt, Rh, Re, Ag, Au, Pd, and Os, and X ₁ or X ₂ is F, Cl, A method for producing magnetic iron oxide particles comprising at least one selected from the group consisting of Br and I, wherein n is an integer of 1 to 6.
The method of claim 1,
The X ₁ is a method of manufacturing iron oxide magnetic particles having a smaller ionic radius than X ₂ .
The method of claim 1,
The step of mixing the particles containing the iron oxide and MX _1n in a solution containing AX _2n ,
After dispersing the particles including iron oxide and MX _1n in a hydrophobic solvent, a solution containing AX _2n is added to a hydrophilic solvent as a solvent, and X _1n is dissolved by heating or microwave. as X _2n A method for producing iron oxide magnetic particles comprising substituting.
The method of claim 1,
MX _1n includes one or more selected from the group consisting of CuF, CuF ₂ , CuF ₃ , CuCl, and CuCl ₂ , and MX _2n is selected from the group consisting of CuBr, CuBr ₂ , CuI, CuI ₂ and CuI ₃ Method for producing iron oxide magnetic particles comprising at least one selected from
The method of claim 1,
A is an alkali or alkaline earth element, specifically, including at least one selected from the group consisting of Li, Na, K, Ru, Cs, Fr, Be, Mg, Ca, Sr, Ba and Ra Method for producing iron oxide magnetic particles.
Iron oxide magnetic particles formed by the manufacturing method of any one of claims 1 to 6.

Images